About this Author

College chemistry, 1983

The 2002 Model

After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases.
To contact Derek email him directly: derekb.lowe@gmail.com
Twitter: Dereklowe

May 19, 2010

Another Set of Eyes

Posted by Derek

Via Avik Roy at Forbes, there's news of a deal between Pfizer and Washington University at St. Louis. The company is giving the university "unprecedented access" to what they say is a list of more than 500 drugs and failed drug candidates, and letting them tear into them in an effort to find out what new uses there might be for both current and failed compounds.

“There are two realities in drug discovery,” explains Don Frail, chief scientific officer of Pfizer’s Indications Discovery Unit. “The majority of candidates tested in development do not give the desired result, yet those drugs that do succeed typically have multiple uses. By harnessing the scientific expertise at this leading academic medical center, the collaboration seeks to discover entirely new uses for these compounds in areas of high patient need that might otherwise be left undiscovered.”

Pfizer's paying Wash. U. $22.5 million as well, which will be well worth it if a single good repurposing idea comes out of the collaboration. Pfizer (or any large drug company) can run through twenty million dollars of expenses on its own without a qualm, so this deal should be no problem. These compounds seem to already have had a lot of work done on them, and will thus have a shorter path through development if something turns up.

I've no idea what the chances of that are, of course - probably not all that great, but it's impossible to be sure about that. I do like the idea of letting a completely different set of eyes go over things, though. One of the biggest problems in a large organization is group-think. People get convinced that something is a hot area because other people seem convinced that it's a hot area, and the same holds true for getting convinced that something's not worth working on.

Look at the way Pfizer convinced itself that Exubera (inhaled insulin) was going to be a huge success, when it was actually a major disaster. On a smaller scale, that sort of thing happens all the time, all over the industry. Projects and ideas rise and fall only partly on their scientific merit - the drug labs are still staffed by human beings, and we're susceptible to all the biases and errors that everyone else is. And it's not like the Washington U people won't have their own biases, but theirs will at least be different.

That brings me back to one of the many reasons that I don't like giant drug company mergers. I think that we need as many different sets of eyes looking at our problems as we can get. The more shots get taken, from all sorts of angles, the better the chance of hitting something. And a huge company, while it does have room for some differences inside it, tends to homogenize viewpoints. The One Big Project with its One Big Compound will get the resources for a given area in the end. It's like when a multiplex theater opens in a smaller town - they tell everyone that with 16 screens they'll be able to bring in movies that otherwise never would play there. But come July, all sixteen screens are probably showing Revenge of the MegaSequel Part II, just to make sure that one's starting every twenty minutes.

This sort of reminds me of the obesity products that Orexigen and Vivus have in Phase III. Both are combinations of existing approved drugs. For example Orexigen's Contrave is a mixture of naltrexone (opioid antagonist) and buproprion (antidepressant). Who would have thought that combination would help with weight loss?

Presumably the compounds Washington U will look at have passed most of the regulatory hurdles and mainly lack efficacy. Considering the enormous cost of taking a drug through Phase I, a deeper examination of the possible uses of these drug sounds like a worthwhile endeavor (to a point of course).

I kind of thought this might have more to do with throwing a bone (a small one) to some of the people in St Loius, who used to work for Pfizer (via Searle) that were recently made redundant. It's sometimes hard to follow the people and see if they overlap. An insider's view would help.

You can try to follow the scientific logic, but I bet there's little here. I'd like to see the compounds. They tell the story. Hopefully it's powder in a bottle and not just pictures like Glaxo recently pawned off in a publicity stunt.

This is interesting. There was a division of Genelogic that was actively trying to sell this Drug re-purposing idea. I interviewed there once.
The scientists were pretty convinced that they were giving good stories for failed drugs and a reason for them to pursue safe compounds. I am wondering whether Wash U will take a different approach. Obviously, Genelogic's division is no longer active and they were saying that Big Pharma was in no mood to buy the idea or to prioritize already failed drugs back in their pipeline.

The cynic in me makes me think whether someone in Pfizer has something to gain for the short term by signing deals in research for innovation or some such criteria...

I'd take this "group-think in pharma" to the next stage. It can lead to being criticism-averse, even when it is constructive. People who put considerable work into something do not want to be told it is/was not worthwhile.

If big pharma is struggling to innovate, then why? This post sums up why so many major companies are struggling. Following fads only make things worse.

The first step is admitting you have a problem. the hard work begins when you try to fix it.

Why don't drug companies do more to put this kind of information out there in some kind of combination of open source/Netlfix Prize where everyone has access to the info (or at least can easily sign onto the appropriate legal agreement governing its use in exchange for access), Pfizer retains rights to the compounds and their derivatives, and anyone who develops a novel use gets a cut of future sales? Basically, why restrict this type of deal to a single academic center? My guess is academic centers would be interested, competitors rather less so, and the garage-based type of entrepreneurs you have noted potentially very interested.

I'd say there are two factors that account for the greater research productivity in small companies.

The first is incentives. When you work for BigCo, the relationship between contributing to the success of the company and getting rewarded can get pretty weak. Nancy discovers a breakthrough new series of compounds with improved PK, then Jim adds a methyl group and becomes the "discoverer" of the clinical candidate. A year later no one remembers Nancy. Going forward, Nancy's priorities shift just a bit, perhaps in a way she is not even aware of.

The same thing can happen at SmallCo, but in this case success potentially means that both Nancy and Jim cash in their options for enough cash to signficantly change their lifestyles, so both are incentivized to keep their eye on the goal. Also, at SmallCo, the company cafeteria only has one table, so they are going to have to look each other in the eye on a regular basis, which helps to keep everybody on the same page.

The second reason is that poorly managed small companies fail and get dissolved. So there is an automatic, relationship-neutral mechanism for stripping resources away from those who do not use them effectively. The extent to which being in charge creates an entitlement of being in charge in the future is probably less in the SmallCo world.

Re: Brian's comment... why would you assume academics would automatically be interested in this? The only possible reason I can think of is "Hey NIH, give me a grant because I have access to some molecules that no-one else has", but that's about it.

Otherwise, let's just call this what it is... big pharma continuing to offload R&D costs onto academia (as they have done for decades), this time by dumping a bunch of failed drugs and calling it a "collaboration". Puhleeze!

What academics really want is access to interesting, novel molecules. Not a bunch of cast-offs, but some really cool new drugs. Of course, most of those are not available to academia, despite asking very nicely (cough... cough... Sirtris... cough).

Its a bit like BP and their "greening" several years ago. They spent $millions actually going green, and then 10 times that amount on advertising to tell everyone about it. Same here... Pfizer is gonna milk this for all its worth, so they can't be accused of holding up competition/academia, and all the while they're keeping the really cool stuff under wraps.

How often has this happened to you: A chemist makes a bunch of compounds for a project and the biological results come back. The best compound is clear. You go to scifinder and see that it is covered by a Pfizer patent for a completely unrelated disease, and was never pursued.

In an ideal world, you say "gee, I wonder if Pfizer has 100 compounds related to the one that I made, sitting on a shelf somewhere? If only I could get to them..."

Then you say... nah... because the last 10 requests you ever made to big pharma went unanswered.

So you go to the second best compound, or seek to get outside of Pfizer's patent space.

I guess Wash U chemists at least have some recourse to Pfizer compounds if they are in that situation. This example may sound very specific and unusual, but it's not, really. Patent protection gained for totally unrelated uses greatly impedes new discovery.

Please can Derek install a spam filter that recognises and rejects any post with 'going forward' in it? It has spread like a disease and to hear it or see it written virtually guarantees I suffer anaphalaxis

Going backward, that's for you Dr Sb, hope it is corrective, I usually agree with Derek, but I don't see how one can support the more eyes is better statement. While it may be true that more shots on goal increases the chance of scoring, the realities are quite different than the analogy.

Investment in pharma and biotech can't be divorced from the economics. The current model of research in bigcos is not producing pipelines that support investment at the same level. I think is a hard truth from a short-term financial perspective, and hard to dispute with evidence from a scientific perspective. So with other drivers, like patent expiry, we see mega-mergers.

Good or bad? Out in the future, if one goes there that is. I am not much of a psychic, too cynical, but I'll offer that my experience. Much of what I experienced and also what I hear from others suggests that bigcos stifle innovation, and the group think of these companies serves to assure the bigco multiplex (pipeline) is playing the same summer blockbusters as all the other pipelines.

So are there really a lot of shots on goal, if the goal is serving unmet need? Not too much, in my opinion. There are a lot of shots at common targets, PI3K, met etc, with a lot of chemistry originating from or bounded by the published patents of competitors, and a lot of chasing established markets with drugs that offer incremental improvements, or none at all.

My hope is that these mergers are disruptive, but ultimately contributing to restructuring of R&D. Yes they could be destructive, but a good drug is still good business, so I doubt it.

Regarding the Pfizer WashU deal, yes low dollar deal, maybe as much PR as true R&D strategy. Why not do more of this? I suggest those that wonder spend some time looking at the way academics are likely to use compounds. Wanting to see an effect, and not sure how things will pan out in their particular bioassay, it is not uncommon for an experiment to be done with drug concentrations in the uM range, in fact often 10-60 uM. I have screened bioassays at scale, and test runs showed that above about 3 uM, hit rates rise to ridiculous levels, so most any biology can be observed with poorly done pharmacology due to loss of specificity in target class, reaching out to new targets, or non-target mediated mechanisms like membrane effects. This can "pollute" your compound with all sorts of activities that complicate further development. So, send them compounds you don't care about, pay little, and hope this deal opens the tech transfer door to new opportunities.

I don't think Pfizer is interested in new leads for further medchem optimization coming out of this collaborative project. They want to find new therapeutic uses for old compounds - on which they have done preclinical development work already...